A Closer Look at Targeted in Metastatic Colorectal - NAMCP Rayes Colorectal Cancer.pdf · A Closer...

1

A Closer Look at Targeted Therapies in Metastatic

Colorectal Cancer

Bassel F. El‐Rayes

Winship Cancer Institute

Emory University

Outline

• New targeted drugs in CRC

– Aflibercept

– Regorafenib

• Review the new data regarding older targeted drugs

– Bevacizumab

– EGFR I

• Discuss how best to use these drugs in CRC

2

Aflibercept

Aflibercept

Fusion protein of key domains from human VEGF receptors 1 and 2 with human IgG Fc¹

Blocks all human VEGF-A isoforms, VEGF-B, and placental growth factor (PlGF)²

High affinity – binds VEGF-A and PlGF more tightly than native receptors

1. Holash J et al. Proc Natl Acad Sci USA. 2002;99:11393-11398.2. Tew WP et al. Clin Cancer Res. 2010;16:358-366.

3

VELOUR Study Design

Primary endpoint: overall survival

Metastatic Colorectal Cancer

R

A

N

D

O

M

I

Z

E

Aflibercept 4 mg/kg IV, day 1 + FOLFIRI q2 weeks

Placebo IV, day 1+ FOLFIRIq2 weeks

1:1 Disease Progression Death

600

600Stratification factors:•ECOG PS (0 vs 1 vs 2)•Prior bevacizumab (Y/N)

Allegra ASCO 2012

Aflibercept + FOLFIRI (n=612)

Placebo + FOLFIRI (n=614)

HRa=0.82 (95.34% CI, 0.71‐0.94)P=0.0032

OS

Est

imat

e

Time, Months

0

0.2

0.8

0.4

1.0

0.6

0 6 123 9 15 21 2718 24 30 3633 39

12.1 mos

13.5mos

Overall Survival

VELOUR : Overall Survival (OS) in ITT Population

Van Cutsem E et al. JCO 2012;30:3499-3506

4



PF

S E

stim

ate

Time, Months

4.7mos

6.9mos

HR=0.76 (99.99% CI: 0.58‐1.00)P=0.00007

Progression‐Free Survival

0

0.2

0.8

0.4

1.0

0.6

0 6 123 9 15 21 2718 24 30

VELOUR Progression Free Survival


1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

HR=0.661 (95% CI, 0.512-0.852)

Progression-Free Survival Overall Survival

HR=0.862 (95.34% CI, 0.673-1.104)1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

PF

S E

stim

ate

Time, Months Time, Months

OS

Est

imat

e

3.9mos

6.7mos

11.7mos

12.5mos

0 6 123 9 15 21 2718 24 30 0 6 123 9 15 21 2718 24 30 33 36



+ Censor

VELOUR PFS and OS in Patients With Prior Treatment With Bevacizumab

+=censor.Tabernero, et al. Presented at: ESMO. 2011 (abstr LBA6).

5

Forest Plots VELOUR


VELOUR Trial: Grade 3/4 Anti‐VEGF Associated Events

Placebo + FOLFIRI

(n = 605)

Aflibercept + FOLFIRI

(n = 611)

Proteinuria 1.2% 7.9%

Hypertension 1.5% 19.4%

Hemorrhage 1.6% 2.9%

VTEPulmonary embolism

6.3%3.5%

7.9%4.6%

Arterial thromboembolicevent 0.5% 1.8%

GI perforation 0.4% 0.5%

Adapted from Allegra C et al. Proc ASCO 2012;Abstract 3505.

6

AE, Safety Population

Placebo + FOLFIRI, % (n=605)

Aflibercept + FOLFIRI, % (n=611)

All Grades Grade 3/4 All Grades Grade 3/4

Diarrhea 56.5 7.8 69.2 19.3

Neutropeniaa

Complicated neutropenia56.3

–29.52.8

67.8–

36.75.7

Asthenic conditions (HLT) 50.2 10.6 60.4 16.9

Stomatitis and ulceration (HLT) 34.9 5.0 54.8 13.7

Thrombocytopeniaa 33.8 1.7 47.4 3.3

Infections (SOC) 32.7 6.9 46.2 12.3

Decreased appetite 23.8 1.8 31.9 3.4

Weight decreased 14.4 0.8 31.9 2.6

Palmar plantar erythrodysesthesia 4.3 0.5 11.0 2.8

Skin hyperpigmentation 2.8 0 8.2 0

Dehydration 3.0 1.3 9.0 4.3

Van Cutsem E, et al. Presented at WCGC. 2011.

VELOUR Most Frequent AEs

Regorafenib

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Regorafenib: an oral multikinase inhibitor1‐3

KIT

PDGFRRET

1. Wilhelm SM et al. Int J Cancer 2011.2. Mross K et al. Clin Cancer Research 2012.3. Strumberg D et al. Expert Opin Invest Drugs 2012.

PDGFR-β

FGFR

VEGFR1-3

TIE2

Regorafenib

Inhibition of neoangiogenesis

Inhibition of neoangiogenesis

Inhibition of tumor microenvironment

signaling

Inhibition of tumor microenvironment

signaling

Inhibition of proliferation Inhibition of proliferation

Biochemicalactivity

Regorafenib IC50mean ± SD nmol/l

(n)

VEGFR1 13 ± 0.4 (2)

Murine VEGFR2 4.2 ± 1.6 (10)

Murine VEGFR3 46 ± 10 (4)

TIE2 311 ± 46 (4)

PDGFR-β 22 ± 3 (2)

FGFR1 202 ± 18 (6)

KIT 7 ± 2 (4)

RET 1.5 ± 0.7 (2)

RAF-1 2.5 ± 0.6 (4)

B-RAF 28 ± 10 (6)

B-RAFV600E 19 ± 6 (6)

CORRECT: Patients with metastatic colorectal cancer treated with regorafenib or placebo after failure of

standard therapy

2:1

Evaluation with CT scan of abdomen and chest every 8 weeks

Van Cutsem ASCO 2012

8

Target Population

•Disease progression during/within 3 months after last administration of or intolerance to approved standard therapies, which had to include:

–Fluoropyrimidine, oxaliplatin, irinotecan

–Bevacizumab

–Cetuximab or panitumumab (if KRAS wild‐type)

Overall survival (primary endpoint)

Primary endpoint met prespecified stopping criteria at interim analysis (1-sided p<0.009279 at approximately 74% of events required for final analysis)


9

Regorafenib significantly improves PFS compared to placebo

Progression‐free survival


Overall response and disease control rates

Best response, % RegorafenibN=505

PlaceboN=255

Complete response 0 0

PR 1.0 0.4

SD 42.8 14.5

Progressive disease 49.5 80.0

DCR* 41.0 14.9

*DCR = PR + SD (≥6 weeks after randomization); p<0.000001

Regorafenib significantly improves DCR compared to placebo


10

Adverse Events

Adverse event, %

RegorafenibN=500

PlaceboN=253

All grades

Grade 3

Grade 4

Grade 5*

All grades

Grade 3

Grade 4

Grade 5*

Hand-foot skin reaction 46.6 16.6 0 0 7.5 0.4 0 0

Fatigue 47.4 9.2 0.4 0 28.1 4.7 0.4 0

Hypertension 27.8 7.2 0 0 5.9 0.8 0 0

Diarrhea 33.8 7.0 0.2 0 8.3 0.8 0 0

Rash / desquamation 26.0 5.8 0 0 4.0 0 0 0

Anorexia 30.4 3.2 0 0 15.4 2.8 0 0

Mucositis, oral 27.2 3.0 0 0 3.6 0 0 0

Thrombocytopenia 12.6 2.6 0.2 0 2.0 0.4 0 0

Fever 10.4 0.8 0 0 2.8 0 0 0

Nausea 14.4 0.4 0 0 11.1 0 0 0

Bleeding 11.4 0.4 0 0.4 2.8 0 0 0

Voice changes 29.4 0.2 0 0 5.5 0 0 0

Weight loss 13.8 0 0 0 2.4 0 0 0

Bevacizumab

11

Phase III Trial of Bevacizumab + IFL as First‐line Therapy for mCRC

*PD = progressive disease.Hurwitz et al. N Engl J Med. 2004;350:2335.

Previously untreated mCRC

N=923

Placebo + IFL (n=411)

Bevacizumab(5 mg/kg, q2w)

+ 5-FU/LV (n=110)

Bevacizumab(5 mg/kg, q2w)

+ IFL (n=402)

Second-line chemotherapy

± Bev

Second-line chemotherapy

± Bev

Second-line chemotherapy,

no Bev

PD

PD

PD

• Primary endpoint: overall survival • Secondary endpoints: PFS, RR, safety, response duration

Overall Survival

Error bars represent 95% CIs.Hurwitz et al. N Engl J Med. 2004;350:2335.

100

OS

(%)

Months

Placebo + IFL: 15.6 monthsBev + IFL: 20.3 monthsHR=0.66, P<0.001

1-year survival74% vs 63%

2-year survival45% vs 30%

20

00

80

40

60

6 12 18 24 30

Placebo + IFL (n=411)Bev + IFL (n=402)

Median survival

12

XELOX + placebo N=350

FOLFOX4 + placebo N=351

XELOX + bevacizumab

N=350

FOLFOX4 + bevacizumab

N=350

XELOX N=317

FOLFOX4 N=317

Initial 2-arm open-label study

(N=634)

Protocol amended to 2x2 placebo-controlled design after bevacizumab

phase III data1 became available

(N=1401)

RecruitmentJune 2003 – May 2004

RecruitmentFeb 2004 – Feb 2005

Bevacizumab and Oxaliplatin‐Based Chemotherapy in

1st Line mCRC NO16966 study design

Cassidy, JCO 2008

Effect of Bevacizumab on PFS: XELOX and FOLFOX Subgroups

XELOX subgroupHR = 0.77 [97.5% CI 0.63–0.94] (ITT)

p = 0.0026

9.37.4

1.0

0.8

0.6

0.4

0.2

00 5 10 15 20 25

Months

PF

S e

stim

ate

XELOX+ placebo N=350; 270 events XELOX+ bevacizumab N=350; 258 events

FOLFOX subgroupHR = 0.89 [97.5% CI 0.73–1.08] (ITT)

p = 0.1871

9.48.6

FOLFOX+ placebo N=351; 277 events FOLFOX+ bevacizumab N=349; 255 events

1.0

0.8

0.6

0.4

0.2

00 5 10 15 20 25

Months

Cassidy, JCO 2008

13

Overall Survival: Chemotherapy ± Bevacizumab (ITT)

ITT = intent to treat.

HR = 0.89 (97.5% CI: 0.76-1.03; P = .0769)

1.0

0.8

0.6

0.4

0.2

0

Months

Su

rviv

al E

stim

ate

0 6 12 18 24 30 36

19.9 21.3

XELOX/FOLFOX4 + bevacizumab n=699 (420 events)

XELOX/FOLFOX4 + placebo n=701 (455 events)

Saltz L, et al. J Clin Oncol 2007;25(18S Part I of II):170s (abstract & poster 4028). Reprinted with permission.

BICC‐C Trial: Addition of Bevacizumab

1st-linemCRC

Irinotecan: 180 mg/m2 (D1) LV: 400 mg/m2 over 2 h (D1)5-FU: 400 mg/m2 (bolus) (D1)5-FU: 2400 mg/m2 (46-h infusion) (D1) q2wks

FOLFIRI + BEV

Irinotecan: 125 mg/m2 (D1, 8) 5-FU: 500 mg/m2 (bolus) (D1, 8)LV: 20 mg/m2 (D1, 8) q3wks

mIFL + BEV

RANDOMIZATION

+ 5 mg/kg bevacizumab q 2wks

+ 7.5 mg/kg bevacizumab q 3wks

Fuchs et al. J Clin Oncol 2007

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27

BICC‐C Period 2: Overall Survival

RegimenMedian OS (Months) 1 Year

HR(95% CI) P Value

FOLFIRI+ BEV 28.0 87% -- --

mIFL + BEV 19.2 61% 2.3(1.3,4.1)

0.007

mIFL + bevacizumab

FOLFIRI + bevacizumab

Pro

po

rtio

n o

f S

ub

ject

sW

ho

Su

rviv

ed

Survival Time (months)

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

10 20 300

1.0

Fuchs et al. J Clin Oncol 2007

Other Studies

• Bevacizumab in combination with capecitabine for the first‐line treatment of elderly patients with metastatic colorectal cancer: Results of a randomized international phase III trial (AVEX).

• FOLFOXIRI plus bevacizumab versus FOLFIRI plus bev as first‐line treatment of metastatic colorectal cancer : Results of the phase III randomized TRIBE trial.

15

BEV + standard

first-line CT (n=820)

Randomise 1:1

Standard second-line CT

BEV + standard second-

line CT

PD

TML‐1 Design

CT switch:Oxaliplatin → IrinotecanIrinotecan → Oxaliplatin

CT switch:Oxaliplatin → IrinotecanIrinotecan → Oxaliplatin

Primary endpoint • Overall survival (OS) from randomisation

Secondary endpoints included

• Progression-free survival (PFS)• Best overall response rate• Safety

•Stratification factors • First-line CT (oxaliplatin-based, irinotecan-based)• First-line PFS (≤9 months, >9 months)• Time from last BEV dose (≤42 days, >42 days)• ECOG PS at baseline (0/1, 2)

Arnold ASCO 2012

TML‐1: Target PopulationInclusion

• PD (≥1 measurable lesion according to RECIST assessed by investigator, documented by CT or MRI), ≤4 weeks prior to start of study treatment

Exclusion

• Diagnosis of PD >3 months after last Bev administration

• First‐line patients with PFS in first‐line of <3 months

• Patients receiving <3 consecutive months of Bev in first‐line

Arnold D, et al. J Clin Oncol 2012;30(suppl; abstr CRA3503).

16

OS: ITT population

OS

est

imat

e

Time (months)

1.0

0.8

0.6

0.4

0.2

00 6 12 18 24 30 36 42 48

CT (n=410)BEV + CT (n=409)

9.8 mo 11.2 mo

Unstratifieda HR: 0.81 (95% CI: 0.69–0.94)

p=0.0062 (log-rank test)

Stratifiedb HR: 0.83 (95% CI: 0.71–0.97)

p=0.0211 (log-rank test)

Median follow-up: CT, 9.6 months (range 0–45.5); BEV + CT, 11.1 months (range 0.3–44.0)

Arnold ASCO 2012

PFS: ITT population

PF

S e

stim

ate

Time (months)

1.0

0.8

0.6

0.4

0.2

00 6 12 18 24 30 36 42

CT (n=410)BEV + CT (n=409)

4.1 mo 5.7 mo

Unstratifieda HR: 0.68 (95% CI: (0.59–0.78) p<0.0001 (log-rank test)

Stratifiedb HR: 0.67 (95% CI: 0.58–0.78)

p<0.0001 (log-rank test)

Arnold ASCO 2012

17

Both VELOUR and TML suggest that continuing antiangiogenic therapy beyond progression is beneficial

KRAS status does not impact antiangiogenic therapy outcome

18

No Impact for KRAS status

0.0

0.2

0.4

0.6

0.8

1.0

0 5 10 15 20 25Duration of PFS (Months)

Proportion Progression Free

0.0

0.2

0.4

0.6

0.8

1.0

0 5 10 15 20 25Duration of PFS (Months)

ProportionProgression Free

Mutant KRAS Wild‐Type KRAS

IFL + Placebo 5.5 mo

IFL + Bev 9.3 mo


IFL + Bev 13.5 mo

HR=0.44; P<0.0001HR=0.41; P=0.0008

Bevacizumab Shows PFS Benefit Regardless of KRAS Status

Rosen. Ann Oncol. 2008;19:vi19 (abstr O‐035).

(n=78) (n=152)

Median PFS Median PFS

19

0.0

0.2

0.4

0.6

0.8

1.0

0 5 10 15 20 25 30Duration of Survival (Months)

Proportion Surviving

Mutant KRAS Wild‐Type KRAS

0.0

0.2

0.4

0.6

0.8

1.0

0 5 10 15 20 25 30Duration of Survival (Months)

Proportion Surviving

Median OS


IFL + Bev 19.9 mo

Median OS


IFL + Bev 27.7 mo

HR=0.58; P=0.04HR=0.69; P=0.26

Bevacizumab Shows OS Benefit Regardless of KRAS Status


(n=152)(n=78)

Relating KRAS Status to Response

0

10

20

30

40

50

60

70

FOLFOX FOLFOX +Bevacizumab

Response Rate (%)

FOLFOX FOLFOX +Bevacizumab

Wild‐Type KRAS P=0.006

Mutant KRASP=0.86

39%

54%

41% 43%

ITTP=0.02

60%

37%

FOLFOX +Bevacizumab

FOLFOX


20

Number at riskCT 165 50 7 2 1 0 0 0Bev + CT 151 80 20 6 3 2 2 0

PFS Estim

ate

1.0

0.8

0.6

0.4

0.2

00 6 12 18 24 30 36 42

Time, Months

4.5 6.4

HR=0.61 (95% CI, 0.49‐0.77);

P<0.0001 (log‐rank test)

Subgroup Findings: Progression Free Survival (PFS) in the KRAS Population

KRASMutantKRASWild‐Type

Interaction test by KRAS status is negative

(P=0.4436)a

0 6 12 18 24 30 36 42

138 40 6 1 1 0 0 0164 73 14 2 1 0 0 0

PFS Estim

ate

1.0

0.8

0.6

0.4

0.2

0

Time, Months

4.1 5.5

HR=0.70 (95% CI, 0.56‐0.89);

P=0.0027 (log‐rank test)

CTBev + CT

. *Genentech/Roche Sponsored StudyVan Cutsem E, et al. Presented at World GI Congress. 2012.

Subgroup Findings: Overall Survival (OS) in the KRAS Population

Number at riskCT 165 122 77 27 11 3 1 0 0Bev + CT 151 126 88 31 18 8 3 0 0

0 6 12 18 24 30 36 42 48

11.1 15.4

HR=0.69 (95% CI, 0.53‐0.90);


OS Estimate

1.0

0.8

0.6

0.4

0.2

0

Time, Months136 107 53 12 5 2 1 1 0164 131 67 18 6 2 0 0 0

0 6 12 18 24 30 36 42 48

10.0 10.4

HR=0.92 (95% CI, 0.71‐1.18);


OS Estimate

1.0

0.8

0.6

0.4

0.2

0

Time, Months

.

Interaction test by KRAS status is negative

(P=0.1266)a

KRASMutantKRASWild‐Type

*Genentech/Roche Sponsored Study

CTBev + CT

21

EGFR I

Khambata-Ford, S. et al. J Clin Oncol; 25:3230-3237 2007

The Ras Mutation

22

Retrospective Studies: KRAS Interaction With EGFR Inhibitors

Study RegimenN (%

mKRAS)

RR

WTMutan

t

Lievre, 2008 Cetuximab 114 (32) 44 0

De Roock, 2008 CT + Cetuximab 113 (41) 41 0

Tejpar, 2008 Irinotecan + Cetuximab 89 (36%) 37 0

Tabernero, 2008 Cetuximab 48 (41) 28 0

Di Fiore, 2007 CT + Cetuximab 59 (37) 12 0

Finocchiaro, 2007 Cetuximab ± CT 81 (40) 27 6

Khambata-Ford, 2007

Cetuximab 80 (38) 10 0

Amado, 2008 Panitumumab 208 (40) 17 0

Lievre. J Clin Oncol. 2008;26:374; De Roock. Ann Oncol. 2008;19:508; Tejpar. ASCO. 2008 (abstr 4001); Tabernero. ASCO GI. 2008 (abstr 435); Di Fiore. Br J Cancer. 2007;96:1166; Finocchiaro. ASCO. 2007 (abstr 4021); Khambata-Ford. J Clin Oncol. 2007;25:3230; Amado. J Clin Oncol. 2008;26:1626.

Phase III Trial: Panitumumab vs BSC in mCRC

• All patients had ≥1% of tumor cells positive for EGFR by immunohistochemical staining

• Eligible patients had progressive disease during or within 6 months of therapy with fluoropyrimidine, irinotecan, and oxaliplatin

Patients with chemotherapy-

refractory mCRCN=463

BSC + Panitumumab 6 mg/kg q2W

N=231

BSC N=232

Van Cutsem. J Clin Oncol. 2007;25:1658.

R

Grade 3/4 Adverse Event BSC + Pan BSC

Rash 7% 0%

Hypomagnesemia 3% <1%

Diarrhea 1% 0%

Fatigue 4% 3%

23

Panitumumab vs BSC in mCRC: PFS

No significant difference in OS between arms (median follow‐up of 72 weeks)

Patients at risk:Panitumumab 231 118 49 31 13 5 1BSC 232 75 17 7 3 1 1

1.0

Pro

po

rtio

n E

ven

t-F

ree

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

Weeks From Randomization0 8 16 24 32 40 48 56

HR=0.54 (95% CI: 0.44, 0.66)

Stratified log-rank testP< 0.0001

PanitumumabBSC

Van Cutsem. J Clin Oncol. 2007;25:1658.

76% of BSC patients crossed over to panitumumab therapy

12.3 wks

KRAS as Biomarker for Panitumumab Response in mCRC: PFS

• PFS log HR significantly different depending on KRAS status (P< 0.0001)• Percentage decrease in target lesion greater in patients with wild‐type KRAS

who receive panitumumab

PFS in Patients With Mutant KRASPFS in Patients With Wild-Type KRAS

1.0

0.9

Pro

po

rtio

n W

ith

PF

S

0.8

0.70.60.50.4

0.3

0.20.1

00 2 4 6 8 10

Median PFS

BSC + Pan BSC Alone 7.3 wks

HR=0.45; P<0.0001

12 14 16 18 20 22 24 26 2830 32 3436 38 4042 44 46 48 50 52

Weeks

Pro

po

rtio

n W

ith

PF

S

1.0

0.90.8

0.70.60.50.4

0.30.20.1

00 2 4 6 8 10 12 14 16 18 20 22 24 26 2830 32 3436 38 4042 44 46 48 50

Weeks

BSC + Pan

BSC Alone

7.4 wks

7.3 wks

HR=0.99

52

Amado. J Clin Oncol. 2008;26:1626.

Median PFS

24

Van Cutsem E et al. JCO 2011;29:2011‐2019

B‐Raf Status

Braf mutant tumours have worse outcome

Benefit from cetuximab was seen in braf mutant and wild type group

Van Cutsem E et al. JCO 2011;29:2011‐2019

25

KRAS G13D

• Mutation in G13D accounts for roughly 6% of CRC

• “Patients with KRAS G13D mutant mCRC appear to benefit from the addition of cet to first‐line CT.” (ASCO 2011)

• “Patients with mCRC whose tumors harbor MT KRAS codon 12 or 13 alleles are unlikely to benefit from panitumumab therapy.” (ESMO 2011)

Influence of K‐ras G13D Mutation

N Response

CT CT/Cet

PFS

CT CT/Cet

OS

CT CT/Cet

Kras wt 845 38.5 57.3 7.6 9.6 19.5 23.5

Odds ratio(95% CI)

21.7 (1.64-2.86) 0.66 (0.55-0.80) 0.81 (0.69-0.94)

Kras G13D 83 22.0 40.5 6.0 7.4 14.7 15.4

Odds ratio(95% CI)

2.41 (0.9-6.45) 0.60(0.32-1.12) 0.80(0.49-1.30)

Kras mutation 450 43.8 30.5 8.5 6.4 17.7 15.5

Odds ratio(95% CI)

0.56 (0.38-0.83) 1.42 (1.10-1.83) 1.14 (0.93-1.40)

Tejpar et al . Abs 3511 ASCO 2011.

26

KRAS G13D

• The differing conclusions maybe due to

– Differences in chemotherapy backbone (FOLFIRI vs FOLFOX).

• For now recommendations:

– Check for G13D mutation

– If present avoid FOLFOX/EGFR‐I combination

How Best To Use These AgentsK‐RAS Wild‐Type

27

Targeted Agents in Frontline Therapy

Tournigand, C. et al. J Clin Oncol; 22:229-237 2004

FOLFOX / FOLFIRI

Colucci, G. et al. J Clin Oncol; 23:4866-4875 2005

28

Anti‐EGFR in First line Treatment of CRC

Trial

Cetuximab Panitumumab

CRYSTAL1

(KRAS WT)(N=350 vs 316)

COIN2

(KRAS WT)(N=367 vs 362)

NORDIC VII3

(KRAS WT)(N=185 vs 194)

PRIME 2034

(KRAS WT)(N=590 vs 593)

Treatment FOLFIRIFOLFIRI + Cetuximab

FOLF/XEL/OX

FOLF/XEL/OX +

Cetuximab

Cont.5-FU/FA/Ox

Cont.5FU/FA/Ox + Cetuximab

FOLFOXFOLFOX +

Panitumumab

OS (mos)P valueHR

20.0 23.50.00930.80

17.9 17.00.601.038

22.0 20.10.661.14

19.7 23.90.170.88

PFS (mos)P valueHR

8.4 9.9 0.00120.70

8.6 8.60.600.959

8.7 7.9 0.661.07

8.6 10 0.010.80

ORR, %

P value

39.7 57.3

<0.001

57 64

0.049

47 46

0.87

48 57

0.02

Bev/Irinotecan‐Based Regimens

Trial AVF2107(N=411 vs 402)

BICC-C(N=57 vs 60)

PACE(N=115)

Treatment IFL +/‐ Bev Bev+ IFL or FOLFIRI Iri/Bev

OS 15.6 vs 20.3<0.001

28.0 vs 19.20.037

20.5

PFS 6.2 vs 10.6<0.001

11.2 vs 8.30.28

11.7

RR 34.8 vs 44.8 57.9 vs 53.3 40%

29

Bev/Oxaliplatin‐Based Regimens

Trial NO169666

(N=701 vs 699)PACE(410)

CARIO 2(N=375)

Treatment FOLFOX/XELOX +/‐Bev

FOLFOX+ Bev XELOX/Bev

OS 19.9 vs 21.20.077

24.5 20.4

PFS 8.0 vs 9.40.0023

On-treatment :7.9 vs 10.4<0.0001

11.4 10.7

RR 38 vs 38 48 40

Frontline Options‐ KRAS Wild‐type

• Oxaliplatin‐based regimen:

– Bevacizumab plus XELOX or FOLFOX

• Irinotecan‐based regimen:

– Bevacizumab plus FOLFIRI

– EFGR I plus FOLFIRI

30

First‐Line Therapy SWOG/CALGB Intergroup Trial: C80405

mFOLFOX6

Or

FOLFIRI

Bevacizumab

Cetuximab

Bevacizumab + Cetuximab

Randomize

Subsequent lines KRAS Wild type

• Choose FOLFIRI/ EGFRI in first line

– FOLFOX/Bevacizumab

– Third line: Regorafenib

31

E3200: Overall Survival

Months

Patie

nts

surv

ivin

g, %

20

180 6 30 360

80

100

40

60

Treatment GroupBevacizumab + FOLFOX-4FOLFOX-4

12 24

10.8 FOLFOX‐413.0 bevacizumab + FOLFOX‐4HR=0.75, P<0.001

Median survival, mo


• Choose FOLFIRI/ Bev in first line

– Second/ Third line

• FOLFOX /Bev (TML Data)

• Irinotecan/ EGFR I

– Fourth line: Regorafenib

32

Cetuximab: Pivotal Trial

• ERBITUX initial dose: 400 mg/m2 (2-hr IV) • Maintenance dose: 250 mg/m2 weekly (1-hr IV) • Irinotecan: same dose and schedule as

patients had previously failed

Patients with EGFR-expressing mCRC who progressed after

irinotecan-based chemotherapy2:1 Randomization

ERBITUX + irinotecan (n = 218)

Stratification• Performance

status• Prior oxaliplatin• Treatment center

Crossover after progression

ERBITUX single agent (n = 111)

Cunningham D, et al. N Engl J Med. 2004;351:337-345.

Cetuximab: Combination With Irinotecan

Time to Progression, All Patients (N = 329)

33


• Choose FOLFOX/ Bev in first line

– Second line

• FOLFIRI/Bev (TML)

• FOLFIRI/ Aflibercept (VELOUR)

– Third line: Irinotecan / EGFRI

– Fourth line: Regorafenib

EPIC Study Design

Cetuximab / Irinotecan

Irinotecan

Failure of Oxaliplatin-Based

TherapySurvival

Stratified by: Study site ECOG PS (0 - 1, 2)

• Primary Endpoint: Survival

• Secondary Endpoints: PFS, RR, DCR, Safety, QoL

• Sample Size: 1298 patients in 221 centers

N = 648

N = 650

Sobrero AACR 2007

34

PR

OP

OR

TIO

N P

RO

GR

ES

SIO

N F

RE

E

0.0

0.2

0.4

0.6

0.8

1.0

0 3 6 9 12 15 18

4.0 mo2.6 mo

MONTHS

HR = 0.692

95% CI = 0.617 – 0.776

CETUXIMAB + IRINOTECAN; N = 648

IRINOTECAN ALONE; N = 650

STRATIFIED LOGRANK P-VALUE = < 0.0001

Progression Free Survival

Sobrero AACR 2007

PR

OP

OR

TIO

N A

LIV

E

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

MONTHS

0 3 6 9 12 15 18 21 24 27 30 33 36 39

HR = 0.975

(95.03% CI = 0.854 – 1.114)

CETUXIMAB + IRINOTECAN; N = 648

Median OS = 10.71 moIRINOTECAN; N = 650

Median OS = 9.99 mo

STRATIFIED LOGRANK P-VALUE = 0.7115

Overall Survival

Sobrero AACR 2007

35

69

201816141210864200.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Prog

ress

ion-

free

Prob

ablili

ty

Months20181614121086420

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Prog

ress

ion-

free

Prob

ablili

ty

Months

HR = 0.73 (95% CI, 0.59, 0.90)Log-rank P value = .004

Eventsn (%)

Median (95% CI) months

Panitumumab + FOLFIRI 178/303 (59) 5.9 (5.5–6.7)

FOLFIRI 203/ 294 (69) 3.9 (3.7–5.3)

KRASwt

Price TJ, et al. ASCO 2010. Abstract 3529.

2nd Line FOLFIRI ± Pmab: PFS

1.0

20181614121086420

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

Months

323028262422 34

Surv

ival

Pro

babi

lity

0.0

1.0

20181614121086420

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

Months

323028262422 34

Surv

ival

Pro

babi

lity

0.0

WT KRAS

HR = 0.85 (95% CI: 0.70, 1.04); Log-rank p-value = 0.12

Eventsn (%)

Median (95% CI) months

Panitumumab + FOLFIRI 200/ 303 (66) 14.5 (13.0 - 16.0)

FOLFIRI 207/ 294 (70) 12.5 (11.2 - 14.2)

Price ASCO 2010

2nd Line FOLFIRI ± Pmab: PFS

36

How Best To Use The Targeted Agents

K‐RAS Mutant

Frontline

• Options:

– FOLFIRI/ Bev

– FOLOFX/ Bev

37

Subsequent lines KRAS Mutant

• Choose FOLFOX/ Bev in first line

– Second line

• FOLFIRI/Bev (TML)

• FOLFIRI/ Aflibercept (VELOUR)


Subsequent lines KRAS Mutant

• Choose FOLFIRI/ Bev in first line

– Second/ Third line

• FOLFOX /Bev (TML Data)


38

Colorectal Cancer‐Future Questions

• Need better biomarkers to decide on how to select the targeted agents.

• Where do the EGFR blocker fit in the KRAS wild type?– Frontline vs. refractory disease

• Potentially resectable stage IV disease – is there a role for targeted agents?

Thank You

A Closer Look at Targeted in Metastatic Colorectal - NAMCP Rayes Colorectal Cancer.pdf · A Closer...

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